Current Organic Chemistry (2009),13, 99-122
L-Ascorbic acid in Organic Synthesis: An Overview
Rama Pati Tripathi*, Biswajit Singh, Surendra Singh Bisht and Jyoti Pandey
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001(India).
Email: [email protected]; Fax: 091-(522)-2623405 / 2623938 / 2629504;
Abstract: L-Ascorbic acid, commonly known as vitamin C is well-known in chemistry since long back. It
has tremendous medical applications in several diseases. However, application of this chiral molecule in
organic synthesis has been neglected earlier. In the later part of twentieth century application of ascorbic
acid has gained momentum in organic synthesis of different molecules of biological importance and of
chemotherapeutic significance. We have given an account of the history, chemistry, biochemistry and
biosynthesis of ascorbic acid and application of this small molecule in organic synthesis. The application
of ascorbic acid in accessing chiral synthons has also been described.
1.1 Introduction
L-Ascorbic acid (Figure 1) is a ubiquitous carbohydrate of vital importance in the living beings. This
vitamin is present in various foods, particularly of plant origin, in quantities, that are several orders of
magnitude higher than those of other vitamins [1].
HO
OH
O
HO
O
OH
Fig. (1). L-Ascorbic acid
Structurally, it is unique and one of the rare compounds containing an acidic hydroxyl group which is
completely dissociated at neutral pH (C-3 hydroxyl, pKa = 4.2). The presence of electron rich C2, C3-enediol moiety in the molecule makes it a member of redox system having both electron donating and
electron accepting properties [8]. At the submolecular level the living process is nothing but a stepwise
transfer of electrons, therefore, ascorbic acid in coherent with other oxidative-reductive system, aids in
maintaining electron transfer process effectively in living organism [2]. It is one of the most important
biomolecules, which acts as antioxidant and radical scavenger [3]. The antioxidant behavior of L-ascorbic
acid is due to its ability to terminate the radical chain reactions and after reaction it is transformed into
non-toxic oxidized product like semidehydro-L-ascorbic acid radical (SDA) and dehydro-L-ascorbic acid
(DA). Semidehydro-L-ascorbic acid radical, disproportionates back to L-ascorbic acid and dehydro-Lascorbic acid (Figure 2).
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Current Organic Chemistry (2009),13, 99-122
HO
OH
O
O
OH
HO
-H+,
O
-e-
O
+
HO
OH +H , +e
O
O
Semidehydro-L-ascorbic acid (SDA)
L-Ascorbic acid
+ e-
+H+, +2eHO
-e-
OH
O
O
O
O
Dehydro-L-ascorbic acid (DA)
Fig. (2). Disproportionation of L-ascorbic acid
It is widely distributed in aerobic organisms where, it play a crucial role in the protection of cellular
components against oxidative damage by free radicals and oxidants that are involved in the development
and exacerbation of a multitude of chronic diseases such as cancer, heart disease, brain malfunction,
aging, rheumatism, inflammation, stroke emphysema and AIDS [4-20]. It also plays crucial role as a
physiological reductant for key enzymatic transformations in catecholamine neurotransmitter, amidated
peptide hormone, and collagen biosynthetic pathways. Several of its derivatives are associated with
numerous biological activities; 5,6-O- modified ascorbic acid derivatives have been found to be effective
anti-tumor agents in various human cancers and induce apoptosis in tumor cells [21-28]; C-2 alkyl
derivatives possess immuno-stimulant activity [29-34]; while C2-O- and C3-O- alkylated derivatives act
as protecting reagents against peroxidation of lipids of the biomembranes [35-36]. Recently, the
chemistry of ascorbic acid has also been exploited in developing strategies for central nervous system
drug delivery [37].
1.2 Biosynthesis of L-ascorbic Acid
Ascorbic acid is synthesized by many vertebrates. The biosynthetic capacity has, however,
subsequently been lost in a number of species, such as teleost fishes, passeriform birds, bats, guinea pigs
and primates including humans, for whom ascorbic acid has thus become a vitamin [38]. Fish, amphibians
and reptiles synthesize ascorbic acid in the kidney, whereas mammals produce it in the liver [39, 40].
Vitamin C is also formed by all the plant species studied so far [41]. Interestingly, different pathways
have evolved for vitamin C biosynthesis in animals, plants and fungi.
The biosynthesis of L-ascorbic acid in animals followed the glucuronic acid metabolic pathway
which is crucial in the metabolism of sugars under both normal and disease states. The glucuronic acid
pathway is regulated by other physiological functions of the body. It is an important mechanism during
detoxification processes in the body and varies from species to species [42-44]. In animals, Dglucuronate, derived from UDP-glucuronate, is reduced to L-gulonate. The latter is converted to its
lactone which in turn, oxidized to L-ascorbic acid, catalyzed by L-gulono-1,4-lactone oxidase (GLO). The
complete biosynthetic pathways [44-46] are shown in (Figure 3).
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Current Organic Chemistry (2009),13, 99-122
ATP
D-Glc
ADP
D-Glc-6-P
1
D-Glc-1-P
2
UDP-D-Glc
3
4
L-GulA
7
D-GlcUA
6
D-GlcUA-I-P
5
UDP-D-GlcUA
8
OH
OH
H
O
OH OH
9
O
Cyt Cox
Catalytic Step
1
2
3
4
5
6
7
8
9
OH H
OH
Cyt Cred
O
O
OH
OH
L-Ascorbic acid
Enzyme
Hexokinase
Phosphoglucomutase
UDP-D-Glucose pyrophosphorylase
UDP-D-Glucose dehydrogenase
D-Glucuronate-1-phosphate
D-Glucurono kinase
D-Glucuronate reductase
Aldonolactonase
L-Gulono-1,4-lactone dehydrogenase
Substrate
D-Glucose
D-Glucose-6-phosphate
D-Glucose-1-phosphate
UDP-D-Glucose
UDP-D-Glucuronic acid
UDP-D-Glucuronic acid-1-phosphate
D-Glucuronic acid
L-Galacturonic acid
L-Gulono-1,4-lactone
Fig. (3). Biosynthetic Pathway of L-ascorbic acid in animals
The deficiency of L-ascorbic acid biosynthesis in certain animals and humans is due to the lack of the
terminal flavor-enzyme, L-gulono-1,4-lactone oxidase (GLO), which completely blocks the production of
L-ascorbic acid in the liver of human beings [42-44]. This oxidizing enzyme is required in the last step of
the conversion of L-gulono-γ-lactone to 2-oxo-L-gulono-γ-lactone, which is a tautomer of L-ascorbic acid
that is spontaneously transformed into vitamin C.
The biosynthesis of L-ascorbic acid in plants is not clearly understood as compared to that in
animals. But recent advances helped to understand its biosynthesis in plants and resolved the several past
contradictions. Biosynthetic pathways generally proceed via GDP-D-mannose and GDP-L-galactose [4247], which was proposed by the Smirnoff group [47]. The Smirnoff-Wheeler-L-ascorbic acid biosynthetic
pathway represents the major route of L-ascorbic acid biosynthesis in plants (Figure 4). The initial step of
L-ascorbic acid biosynthesis in plants is also utilized for the synthesis of cell wall polysaccharide
precursors, while later steps following GDP-L-galactose are solely dedicated to plant biosynthesis of Lascorbic acid.
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Current Organic Chemistry (2009),13, 99-122
ATP
D-Glc
ADP
1
D-Glc-6-P
D-Fru-6-P
2
D-Man-6-P
3
4
PPi
GDP-L-Gal
GMP
GDP-Man
6
7
GTP
D-Man-1-P
5
OH
O
NAD NADH HO
L-Gal-1-P
8
L-Gal
H
HO
9
Pi
O
ox
HO
H
O
Cy
HO
HO
tC
r ed
Cy
tC
10
O
OH
HO
L-Ascorbic acid
Catalytic Step
1
2
3
4
5
6
7
8
9
10
Enzyme
Hexokinase
Phosphoglucose isomerase
Phophomannose isomerase
Phophomannose mutase
GDP-Mannose pyrophoshorylase
GDP-Mannose-3,5-epimerase
GDP-L-Galactose
L-Galactose-1-phosphate phosphatase
L-Galactose dehydrogenase
L-Galactono-1,4-lactone dehydrogenase
Substrate
D-Glucose
D-Glucose-6-phosphate
D- Fructose -6-phosphate
D- Mannose -6-phosphate
D- Mannose -1-phosphate
GDP-D-Mannose
GDP-L-Galactose
L-Galactose-1-phosphate
L-Galactose
L-Galactono-1,4-lactone
Fig. (4). Biosynthetic Pathway of L-Ascorbic acid in plants
1.3 Discovery and history of L-ascorbic Acid
All living organisms either make ascorbic acid or get it in their food stuffs. The enzyme systems for
the production of vitamin C is of ancient origin and were formed very early in the development of life
process on this planet, probably the most developed forms were still primitive unicellular forms. The
deficiency syndrome of vitamin C in animals is scurvy. Symptoms of scurvy include anorexia, anaemia,
arthralgia, bleeding gums, coiled hair, depression, dry eyes and mouth (Sjogren’s Syndrome), eccymosis,
follicular hyperkeratosis, fatigue, frequent infections, impaired wound healing, inflamed gums, joint
effusions, myalgia, muscle weakness, perifollicular hemorrhages, and petechiae. The later stage
conditions include patients exhibiting extreme exhaustion, kidney and pulmonary problems, as well as
diarrhea, eventually leading to death. The necessity to take fresh animal flesh or plant food in the diet to
prevent scurvy disease was known since ancient times. Eber’s Papyrus, an ancient Egyptian medical
treatise in 1,500 B.C., described scurvy as a disease characterized by spongy and bleeding gums and
bleeding under the skin. Around 400 BC, Hippocrates, a Greek physician known as the founder of
medicine, preached against one sided nutrition and described how good a daily and healthy diet rich in
foods that are known today to contain great amount of vitamin C could help to prevent diseases such as
scurvy. In 1200 AD, the Crusaders were plagued with scurvy. From 1492 to1600, world exploration was
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Current Organic Chemistry (2009),13, 99-122
threatened by scurvy. Ferdinand Magellan, a Portuguese sea captain around 1520, lost 80% of his crew to
scurvy. Also Vasco de Gama a Portuguese conquistador was the first to sail across the African coast on
his way to India in 1492 and lost 100 of his 160 crew to scurvy. Scurvy was severe threat to thousands of
soldiers and sailors alike and many died of the disease during military campaign and lengthy ocean
voyages, respectively, until in 1720, when physician J.G.H. Kramer found that fresh herbs and lemons
cured the disease [48-77].
In 1746, James Lind, a British naval surgeon on H.M.S. Salisbury conducted a controlled test on 12 of his
seamen suffering from the debilitating effects of scurvy and became the first person to give a scientific
basis for the cause of scurvy. In 1753, James Lind published the results of his famous finding in his 400page book, Treatise of the scurvy, where for the first time he established the benefit of citrus fruits in
combating scurvy and by 1795, royal navy had mandated the use of lime juice or other citrus fruits as a
scurvy preventative. In 1912, for the first time, the vitamin hypothesis was suggested by polish American
chemist Funk, part of which stated that scurvy was a deficiency disease caused by the lack of unknown
water soluble substance called the anti-scorbutic factor. In 1920, Sir Jack Cecil Drummond, the first
professor of biochemistry in the University of London, suggested calling this substance as Vitamin C,
because man, guinea pigs, and certain monkeys unlike other mammals cannot make their own ascorbic
acid. This unknown water soluble anti-scorbutic substance was isolated from Ox adrenal cortex (and
various plants) in 1928 by Hungarian biochemist research team of Joseph L. Svirbely and Albert Von
Szent Gyorgyi. In autumn of 1931, this reducing substance with molecular formula C6H8O6, which he
named hexuronic acid, was unequivocally proven in experimentation as the powerful anti-scorbutic
substance, and that the anti-scorbutic activity of plant juices corresponded to their hexuronic acid content.
About the same time, the Americans Glen King and William A. Waugh also reported crystals from lemon
juice, which were actively anti-scorbutic and resembled hexuronic acid. In 1932, Albert Von Szent
Gyorgyi and British chemist Sir Walter Norman Haworth subsequently renamed hexuronic acid as
ascorbic acid. In 1933 main features of the constitution of ascorbic acid and its formula as a lactone of 2keto-L-gulonic acid, capable of reacting in various tautomeric forms, was first announced from the
University of Birmingham. Almost at the same time, the Polish Tadeous Reichstein, in Switzerland, as
well as Haworth’s group independently achieved the synthesis of vitamin C. The synthetic form of
vitamin was identical to the natural form and this made possible the cheap production of vitamin C on
mass scale. Three patent applications were filed in 1935 and patents were granted in 1935 and 1940. Thus
American biochemist and chemical engineer Dr. Irwin Stone obtained the first patent on an industrial
application of ascorbic acid. Sir Walter Norman Haworth and Paul Karrer shared the Nobel Prize for
Chemistry in 1937 partly due to their work in determining the structure and synthesis of vitamin C. Also
in 1937, Albert Von Szent-Gyorgyi was awarded the Nobel Prize for his studies of the biological
functions of vitamin C [48-77].
1.4 Sources of L-ascorbic Acid
The main sources of L-ascorbic acid are plant and animals derived products. The ubiquitous nature
of L-ascorbic acid throughout the human body emphasizes its daily requirement and vitality as nutrients
for healthy maintenance [78-80]. Its half life in humans is 14-40 days after normal intake and a vitamin C
free diet in humans develops scurvy in about 3-4 months [81].
The vast majority of plants and animals such as amphibians, reptiles, birds, and mammals are known to
synthesize their own vitamin C. All algal classes can synthesize vitamin C from glucose or other sugars.
All higher plant species can also synthesize vitamin C and thus make it prevalent in surrounding food
sources [82]. For example, large concentrations of vitamin C are found in fruits such as oranges,
grapefruits, tangerines, lemons, limes, papaya, strawberries and cantaloupe. Also many vegetables are
known to pack in vitamin C and these include tomatoes, broccoli, green and red bell peppers, raw lettuce
and other leafy greens. A complete listing of every food containing vitamin C according to USFDA food
database is available through the Vitamin C Foundation [82].
1.5 Physico-chemical properties of L-ascorbic Acid
The physiological activity of L-ascorbic acid stems from its basic functional structure. It is a
five-membered lactone sugar acid and its C3 and C2- enolic hydroxyl groups may dissociate to form a
dibasic acid. The 2, 3-enediol moiety conjugated with the lactone carbonyl group, results the C3 hydroxyl
proton significantly acidic (pK1= 4.25) as compared to the C2 hydroxyl proton (pK2 = 11.79) [83]. The
2,3-enediol moiety of L-ascorbic acid enables it to donate one or two electrons (reducing equivalents) and
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Current Organic Chemistry (2009),13, 99-122
form a comparatively stable oxidized intermediate (semidehydro-L-ascorbic acid) and the finally oxidized
product (dehydro-L-ascorbic acid). This phenomenon of electron donation is responsible for most, but not
all the chemical and biological functions of L-ascorbic acid. The other two -OH at C5 and C6 behave as
alcoholic groups. They react with aldehydes and ketones to give cyclic acetals and ketals, respectively.
Due to the presence of two asymmetric centers at C4 and C5 it possesses a positive value of optical
rotation. The optical rotation is not significantly affected by the acidity of the solution, but in contrast it
varies greatly with alkalinity, increasing over +160° in 2N NaOH solution [84]. A number of physical
properties of L-ascorbic acid are listed in Table 1 [85, 86].
Insert table 1 here.
Chemical reactions of L-ascorbic Acid
1.6 Chemoselective alkylations of L-ascorbic Acid
Taking into account of the acidity of four hydroxyl groups (pKa value) and their steric
environments in L-ascorbic acid, alkylation studies have been carried out under different experimental
conditions. The four hydroxyl groups show different reactivity toward electrophiles under basic reaction
conditions. These hydroxyl groups impart highly hydrophilic character to it and therefore, insoluble in
organic solvents. Because of its hydrophilic character it has been modified to synthetically useful
intermediates which are soluble in organic solvents. One of such derivative, 5,6-O-ketal or 5,6-O-acetal,
are soluble in organic solvents. The protection of 5 and 6 -OH groups also limits their interference during
reaction, involving the C-2 and C-3 enol hydroxyls. These derivatives 5,6-O-isopropylidene-L-ascorbic
acid (2) has been prepared, using different methods [87], but the simplest method was to dissolve Lascorbic acid (1) in excess acetone containing a catalytic amount of acetyl chloride [88] (Scheme 1).
HO
OH
O
HO
O
OH
CH3COCH3
O
O
O
O
AcCl, 80-85%
HO
1
2
OH
Scheme 1.
1.6.1. 3-O-Alkylation of 5,6-O-isopropylidene-L-ascorbic Acid
During reactions of 5,6-O-isopropylidene-L-ascorbic acid (2) with various electrophilic reagents
under mild basic condition should predominantly occur at the C3-OH position in comparison to C2-OH.
This is primarily due to the preferential deprotonation of C3-OH over C2-OH to produce monoanion.
Further, the electron density distribution pattern of the negatively charged monoanion, between C3-O- and
C1-carbonyl of the lactone ring with little density on C2-OH [89]. Therefore, the reactions of 5,6-OH
protected ascorbic acid with electrophilic reagents under mild basic conditions preferably occur at the C3OH position as experimentally observed [90, 91]. However, the electron density at the C-2 carbon of
monoanion is significantly higher than that of the C2-OH, which renders the C-2 position of the
monoanion susceptible to electrophilic reagents. Therefore, its C-2 alkylated products were also observed
as minor products during alkylation of (2) under mild alkaline conditions [89, 90].
The 3-O-alkylation of 5,6-O-isopropylidene ascorbic acid has been studied in detail by Kulkarni and
Thorpate [90]. During alkylation of 5,6-O-isopropylidene ascorbic acid with alkyl halides under basic
condition 3-O-alkyl derivative is major product while small amount of C-2 alkyl and 2,3-di-O-alkyl
products were also observed (Scheme 2). The effects of solvent and temperature on the formation of
alkylated products have also been elucidated.
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Current Organic Chemistry (2009),13, 99-122
O
O
O
HO
2
O
O
O
O Method (A-C)
O
O
O
O
O
+
OH
RO
3
O
O
O
O
+
OH
RO
4
OR
R
O
5
OH
Method A: 2, Et3N, RBr, Dry Methanol, 3-6 hrs,
Method B: 2, anhyd. K2CO 3, RBr, THF:DMSO (1:1), 1-3 hrs,
Method C: 2, anhyd.K2CO 3, RBr, acetone, 1h, Method D: 2, anhyd. K 2CO 3, RBr, dry acetone, 1h, reflux.
Scheme 2.
The alkylation of 5,6-O-isopropylidene-L-ascorbic acid (2) in dry acetone shows better selectivity for 3O-alkylation as compared to reaction in THF:DMSO (1:1) at ambient temperature or under triethylaminemethanol. Refluxing 3 in acetone with excess of various alkylating agents in presence of K2CO3 furnished
corresponding 2,3-di-O-alkyl product 6 (Scheme 3).
O
O
O
O
O
R1X (excess)
O
anhyd. K2CO 3, dry Me2CO
30 min
OH
RO
O
3
RO
6
O
OR1
Scheme 3.
Wimalasena et.al. [91] also carried out 3-O-alkylation in THF: DMSO (9:8) in the presence of K2CO3 to
get the alkylated products 3 and 5 respectively.
1.6.2 Direct 3-O-alkylation of L-ascorbic acid under Mitsunobu condition
3-O-Alkylation of L-ascorbic acid under Mitsunobu reaction condition [92] with different alkyl and allyl
alcohols is shown below (Scheme 4).
HO
OH
O
HO
O
OH
DEAD
HO
OH
HO
O
Ph 3P, THF/DMF
-78o C
O
Ph3P
1
7
Scheme 4.
6
O
O
OH
O
ROH
RO
O
OH
8a-e
R
Me (8a)
Propyl (8b)
Octyl (8c)
Allyl (8d)
Benzyl (8e)
Yield%
77
63
72
72
64
Current Organic Chemistry (2009),13, 99-122
Application of Mitsunobu reaction condition [92] to prepare 3-O-allyl-2-O-methyl-L-ascorbic acid in one
pot from L- ascorbic acid and allyl alcohol has also been elucidated as shown in Scheme 5.
OH
HO
OH
HO
O
O
HO
O
1. DEAD, Ph3P, THF, allyl alcohol
2. DEAD, Ph 3P, CH3OH, -78 oC
OH
O
1
O
OCH 3
9 (34%)
Scheme 5.
Further, a number of 3-O-silane derivatives of L-ascorbic acid (11a-d) have also been prepared, by the
reaction of L-ascorbic acid (1) with O-silyl chlorides [93, 94] as shown in Scheme 6. In this synthesis, the
versatility of the Mitsunobu reaction allowed the intermolecular dehydration to take place under mild
conditions, resulting in the ether linkage in compounds 11a-d. The beauty of this synthesis is the absence
of any protecting group on the other hydroxyls. Further, the yield of the products obtained is independent
of the alkyl chain length of the above O-silyl chlorides.
HO
OH
O
HO
OH
O
HO
O
+ HO
n Si Cl
Ph3P, DEAD, THF
Cl
OH
OH
n O
11 a-d
Si
10 a-d
1
O
11a
11b
11c
11d
n=1
n=2
n=3
n=4
(51%)
(31%)
(42%)
(40%)
Scheme 6.
1.6.3 Direct 2-O-alkylation of 5,6-O-isopropylidene-L-ascorbic Acid
Direct alkylation of C2-OH in 5,6- O -isopropylidene-L-ascorbic acid is difficult due to much
less electron density at C2-OH as compared to C3-OH. Wimalasena et.al. [89] have prepared exclusively
the derivative of L-ascorbic acid and 2-O-alkyl derivative (12) of 5,6-O-isopropylidene-L-ascorbic acid
by the reaction of 5,6-O-isopropylidene-L-ascorbic acid (2) with alkyl halides in the presence of 2 eq. of
potassium tert-butoxide (t-BuOK) in DMSO/THF (3:2) at -10 °C (Scheme 7).
O
O
O
O
HO
2
O
O
2 equiv. t-BuOK/RBr
DMSO/THF/-10 °C/3h
OH
O
HO
O
OR
12
Scheme 7.
Taking the advantage of electron density at C and O atoms of the L-ascorbic acid, the dianion of Lascorbic acid was generated by reacting 2 eq. of potassium tert-butoxide (t-BuOK) in DMSO/THF (3:2) at
-10°C. The reaction of dianion, so generated, with 1 eq. of activated or unactivated electrophilic alkylating
agents gave the respective 2-O- alkyl ascorbic acid derivatives in good yields.
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Current Organic Chemistry (2009),13, 99-122
1.7 2-C and 3-C Allylation of 5,6-O-isopropylidene-L-ascorbic acid: thermal Claisen rearrangement
[91,95]
A convenient synthesis of 5,6-O-isopropylidene-2-allyl-3-keto-L-galactono-γ-lactones (14) and 5,6-Oisopropylidene-3-allyl-2-keto-L-galactono-γ-lactones (16) involve thermal claisen rearrangement of the
corresponding 3-O- and 2-O-allyl derivatives of 5,6-O-isopropylidene-L-ascorbic acid (13) and (15)
respectively.
O
O
O
O
O
O
Reflux/ toluene
O
13
R1
O
OR2
OR2
O
O
R1
14
R1 = H, CH3, C6H5
R2 = H, Ac, allyl
O
O
O
R 2O
O
O
Ref lux/ toluene
R1
O
15
O
O
R1
O
OR2 O
16
R1 = H, CH3, C6H5
R2 = H, Ac, CH3
Scheme 8.
In contrast to the smooth rearrangement of C3-O-allyl ascorbic acid derivatives under relatively mild
conditions whereas, the rearrangement of their C2-O-allyl counterparts (Scheme 8) is much slower and
requires much drastic reaction conditions. The relative difficulty for the rearrangement of C2-O-allyl in
comparison to C3-O-allyl derivatives could be due to a combination of steric and electronic effects.
Firstly, the steric constraints on the transition state for the C2-O to C-3 allyl migration are more
pronounced relative to that of the C3-O to C-2 allyl migration, due to the presence of a bulky 1,2-Oisopropylidene-1,2-ethanediol moiety at the C-4 in the substrate. Secondly, the relatively high lability of
C3-O- allylic ether linkage compared to that of the C2-O-allylic ether linkage is due to the direct
interaction of the C3-O with the conjugated enone moiety which also facilitates the rearrangement to
produce the thermodynamically more stable C2- allylated products.
1.8 Diastereoselective transannular [2+2] photocycloaddition
Sebastein Redon and Oliver Piva [96] reported the synthesis of 2-, 3-O-alkenyl derivatives of 5,6-Oisopropylidene-L-ascorbic acid (19a-c) via diastereoselective transannular [2+2] photocycloaddition. Thus
compounds (17a-c) were respectively converted into cyclic bisethers (19a-c) in the presence of catalytic
amounts of first generation Grubbs’ catalyst (18). The results are shown in Scheme 9.
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Current Organic Chemistry (2009),13, 99-122
PCy 3
Cl Ru
Ph
Cl
PCy 3
R R
O
O
O
X O
n
O
R R
O
O
O
18(5 mol%)
O Y
n
CH2Cl 2
O
O
Y
X
n
17a,b (R, R = CH 3, CH3)
17c (R, R) = - (CH2) 5-
Substrate
O
n
19a-c
n
X, Y
Product
% yield
17a
CH2/CH2
0
19a
50
17b
CH2/CH 2
1
19b
66
17c
CH2/CH2
1
19c
55
Scheme 9.
Further, a transannular cycloaddtion of the above metathesis product (19a) by its irradiation at 254 nm at
5°C, in dichloromethane or in acetonitrile at low concentration (10-2M) resulted into a
tricyclo[2.2.0]octane (20a), a highly unfavorable product. Similarly, irradiation of 19b afforded two
diastereoisomers 20b and 21b while irradiation of 19c gave the diastereoisomers 20c and 21c
respectively. The results are shown in Scheme 10.
R'O
R'O
O
O
R'O
R'O
O
hu
O
O
n
O
CH 3CN, 5 o C
+
O
O
n
n
20a-c
19a-c
Substrate
R'O
O
O
n
n
R'O
R'
n
O
O
n
21a-c
Product 20/21 (ratio)
20a
Overall Yield (%)
50
19a
Isopropylidene
0
19b
Isopropylidene
1
20b/21b(47/53)
66
19c
Cyclohexylidene
1
20c/21c(59/41)
55
Scheme 10.
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Current Organic Chemistry (2009),13, 99-122
1.9 The Paterno-Buchi Reaction of L-ascorbic Acid
The irradiation of a solution of 5,6-O-isopropylidene-2,3-di-O-alkyl ascorbic acid derivatives
(22) and benzaldehyde in benzene under UV light through a pyrex filter resulted in the oxetanes 23a
and 23b in moderate to good yields [98]. The results are shown in Scheme 11.
O
O OMe
OR
O
O
O
O
O
O
MeO
O
+
Ph
(a) hv, C6H6, N2,
H
+
H
30-60 h
OR
O
O
22 R = Me
24 R = Benzyl
O OMe OR
O
O
H
H
H
Ph
Ph
O
23b R = Me (25%)
25b R = Bn (28%)
23a R = Me (60%)
25a R = Bn (57%)
Scheme 11.
The preferred mode of attack for the photoexcited carbonyl group of benzaldehyde on enediols 22
and 24 would presumably be from the less hindered α face, with aldehyde proton oriented in endo
fashion. Therefore, the phenyl residue and alkoxy groups on the oxetane ring are in cis orientation in
the products 23a, 23b, 25a and 25b.
1.10 Photoreduction of quinones with 5,6-O-isopropylidene-L-ascorbic Acid
L-Ascorbic acid is known to reduce different systems [99], including inorganic compounds [100] under
photolytic condition. It is also reported [101] to reduce quinones in a ground state reaction. Irradiation of a
mixture of 5,6-O-isopropylidene-L-ascorbic acid (2) and quinones (26) in 1,2-dimethoxy ethane (DME),
resulted in their respective hydroquinones (28) [102] (Scheme 12).
O
O
O
O
HO
O
OH
2
R
+
hu, DME
O
OH
O
O
25 °C
O
O
26
27
O
O
+
R
OH
28
Scheme 12.
1.11 Photooxygenation of L-ascorbic acid derivatives
The singlet oxygen reacts with L-ascorbic acid (1) at low temperature in an ene-type reaction
[103] to give two unstable hydroperoxy ketones (29) and (30). The latter rearranges to
hydroperoxydehydroascorbic acid (31) by intramolecular cyclisation [104]. Hydroperoxide (31), in turn, is
converted to the oxalic acid and L-threonolactone (32) on warming and hydrolysis (Scheme 13).
Kwon et al. [105] have shown that photooxygenation of 3-O-methyl-5,6-O-isopropylidene-Lascorbic acid (33) at ambient temperature in methanol using rose bengal as a sensitizer resulted in 80% of
the oxalate methyl ester (34) and 20% of the corresponding acid (35) (Scheme 14). The oxalic acid
monoester was easily converted to methyl ester (34) by reaction with CH2N2 in methyl alcohol.
10
Current Organic Chemistry (2009),13, 99-122
HO
OH
O
HO
HO
O
1O
OH
2
OH
HOO
1
O
O
OH
OH
30
O
HO
O
+ Oxalate
O
O
OOH
O
O
29
OH
HO
OH
HO
O
O
O
OOH
OH OH
31
32
Scheme 13.
R'
O
HO
O
OH
33
R' = -CHO(CH 3)2OCH2
Rose Bengal, O 2,
hn, RT
CH 3OH
R'
H3CO
O
O
CH 2N 2
R'
H3CO
O O OCH 3
34
O
OO
O
OH
35
Scheme 14.
1.12 Reaction of p-hydroxy benzylalcohol derivatives with L-Ascorbic Acid
L-Ascorbic acid (1) on reaction with p-hydroxy benzyl alcohol (36) yields 2-(p-hydroxybenzyl)3-ketohexulosonic acid lactone (37) [106]. The reaction proceeds via protonation of the benzylic alcohol
moiety with ascorbic acid followed by elimination of water which is triggered by phenol. The resulting
protonated quinine methide (38) adds to the conjugate base of ascorbic acid (1) to yield a bicyclic product
(37) (scheme 15).
11
Current Organic Chemistry (2009),13, 99-122
OH
OH
O
HO
O
OH
OH
OH
O
O
+
O
OH
1
HO
+
HO
OH
OH
OH2
36
OH
H
38
O
O
O
OH
HO
37
Scheme 15.
The alkylation occurs from the less hindered α-face of (1) as dictated by C-5,6 side chain. The
total syntheses of delesserine, methyl rhodomelol and rhodomelol have also been accomplished using this
methodology [106].
1.13 Reaction of Vanilmandelic Acid derivatives with L-Ascorbic Acid
Preobrazhenskaya and co-workers [107] have reported that the incubation of vanilmandelic acid (39a)
and L-ascorbic acid 1 at pH 1 and 50-60 °C for 5-days resulted in the formation of 2-hydroxy-3-(4hydroxy-3-methoxyphenyl)-4-hydroxymethylcyclopent-2-en-one (45) in 10% yield, about 20% of vanillin
and traces of 2-furancarboxylic acid (47) are also obtained (Scheme 16). The same reagents in 75%
aqueous ethanol at pH 1 gave 41% of ethyl vanillylmandelate (39b) and about 58% of (47). Under the
same conditions methyl vanilmandelate (39c) and ascorbic acid gave (47) as the main product along with
the traces of (47) and vanillin as shown in Scheme 16.
The retrosynthetic analysis suggests that 2-C-(carboxy)(4-hydroxy-3-methoxyphenyl)methylation of the
L-ascorbic acid moiety in the presence of an acid give the desired framework (40a) in the same way as the
interaction of L-ascorbic acid with 4-hydroxyphenyl alcohol described earlier [106]. The intermediate
(40a) appears to be unstable as its lactone ring is opened to give β-keto acid (41a), which easily
decarboxylates to a ketone intermediate (43a) and the latter, on dehydration gives the intermediate γdiketone (44a). The γ-diketone, on further reactions viz. dehydration, decarboxylation and cyclization
produces 2-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-4-hydroxymethylcyclopent-2-en-one (45). The
above β-keto ester (44b or c) on reaction with L-ascorbic acid resulted in esters (39b or c) respectively.
Further, dehydrative cyclization via β-keto ester (46) results in 2-furancarboxylic acid (47) and alkyl 4hydroxy-3-methoxyphenyl acetate (48) in good yields (Scheme 16).
12
Current Organic Chemistry (2009),13, 99-122
H3CO
HO
CHOHCOOR
+
HO
39
CH 3
O
CH2OH
OH
HC
O
O
1
O
OH
O
CHCOOR
OH
OCH3
OH
40
COOH
HO
O
CHCOOR
CHOH
HOHC
-CO2
42a-c
O
CHCOOR
-H 2O
HOHC
CHOH
CHCOOR
-2H 2O
HOHC
R=Alkyl
CH2
OH
OCH 3
HOHC
OH
OCH3
CH2OH
41a-c
O
CHCOOR
CHOH
HOHC
OH
OCH3
CH2OH
OH
O
OH
OC
CH 2OH
OCH 3
CH 2OH
43a-c
44a-c
O
-H 2O, -CO 2
HOH 2C
OC CHCOOR
ROOCH2C
H 2O
+
O
OH
OH
OCH3
COOH
OH
OH
OCH3
OCH 3
47
48b,c
45
46b,c
R = H (a), Et (b), Me (c)
Scheme 16.
1.14 Reaction of (indol-3-yl) ethanediol with L-ascorbic acid
Reaction of (indol-3-yl)ethanediol (49) [109] and L- ascorbic acid (1) in aqueous ethanol under ambient
condition led to formation of a mixture of compounds 50, 51
13
Current Organic Chemistry (2009),13, 99-122
OH
HO
OH OH
N
H
O
HO
OH
Ind
O
O
O
O
O
HO
O
OH
Ind
H
53
1
OH
O
51
O
O
O
O
OH
Ind
H
54
O
H
OH
OH
HO
HO
OH
Ind
O
H
OH
O
OH
O
HO
50
HO
49
OH
HO
O
+
O
52
COOH
H
Ind
OH
HO COOC2H5
H
HO
O
O
Ind
55
Scheme 17.
and 52. The latter on further incubation with 2% ethanolic HCl at ambient temperature led to a mixture of
ketal derivatives 53, 54 and 55 respectively as shown in Scheme 17.
1.15 Synthesis of (Z)-alkylidene-2, 3-dimethoxy butenolides and their reactions:
A simple and efficient synthesis of (Z)-alkylidene-2,3-dimethoxy butenolide from L-ascorbic
acid has been reported by Khan et al [110]. It involves deketalization of 2,3-O-dimethyl-5,6-Oisopropylidene-L-ascorbic acid (56) with an acid to give the respective diol (57). The latter on reaction
with p-toluene sulphonyl chloride led to the formation of an intermediate ditosyl derivative (58) which on
reaction with different nucleophiles yielded the respective γ-(Z)-alkylidene-2,3-dimethoxy butenolides
(59) (Scheme 18).
14
Current Organic Chemistry (2009),13, 99-122
OH
HO
O
HO
O
O
O
Me2C(OMe)2/H +
acetone
OH
O
O
HO
1
O
O
Me2SO4/K 2CO3
acetone/ref lux
MeO
OH
2
O
O
TsO
O
MeO
Nu-
OMe
OTs
O
MeO
O
OMe
HO
2 eq TsCl/Py
RT, 30h
MeOH/H 3O +
OH
O
MeO
O
OMe
57
58
59a-e
OMe
56
ref lux, 3h
Nu
O
Nu = (EtO 2C) 2HC- , (EtO 2C)(SO 2Ph)HC (EtO2C)(COMe)HC-, N3- , AcO-
Scheme 18.
Mechanistically, the formation of (59) from (58) is believed to involve a two-step reaction pathway in
which the first step is an elimination (E2) process that produces an exocyclic allylic tosylate which on the
subsequent reaction undergoes SN2 reaction with the nucleophile.
TsO
OTs
O
MeO
TsO
O
OMe
O
E2
MeO
Nu
O
Nu
OMe
SN2
O
MeO
O
OMe
Fig. (5).
1.16 Synthesis of triene systems from L-ascorbic acid and their application: oxaspiro [4, 5]
decanenones
L-Ascorbic acid (1) has been transformed into the (Z)-butenolide acetate (59e) [110] via a multistep
process. The intermediate 59e on acid catalyzed deacetylation results in an allylic alcohol (60), which on
oxidation with pyridinium chlorochromate (PCC) yielded the (Z)-butenolide aldehyde (61) in good yield
(Scheme 19) [111].
15
Current Organic Chemistry (2009),13, 99-122
HO
OH
O
HO
O
OH
1
AcO
O
ref . 96
MeO
O
OMe
HO
O
MeOH/H 3O +
O
MeO
59e
OMe
60
DCM
PCC/NaOMe
OHC
O
MeO
Scheme 19.
O
OMe
61
The (Z)-butenolidyl aldehyde (61) has been reacted smoothly with a variety of ylides in THF at -78 °C to
give the trienes (62a-e) shown in Scheme 20. The trienes in the above reactions either have the (E)geometry exclusively (62b and 63c) or the compounds with (E)-geometry were the major product. Diels
Alder cycloaddition reaction (62a) with one equivalent of diethyl maleate (63) in 1,1,2,2tetrachloroethane in an autoclave at 140 °C and 30 atm pressure for 33 h, did not give the cycloaddition
product instead of two molecules of (62a) itself undergo Diels Alder reaction to give two oxaspiro [4,5]
decanones (±) (65) and (±) (66) (Scheme 20).
16
Current Organic Chemistry (2009),13, 99-122
R
OHC
O
MeO
O
O
i
OMe
MeO
61
O
OMe
62. a R = H
b R = (E) C3H 7
c R = (E) CO2Et
d R = (Z) CO 2Et
e R = (E) Ph
EtO 2C
O
CO 2Et
O
MeO
OMe
62a
MeO
CO2Et
MeO
63
OMe
MeO
64
ii
+
CO2Et
O
O
O
O
O
MeO
O
OMe
65, 66
Scheme 20.
(i) RCH2PPH 3Br/BuLi/THF/ -78 °C (ii)Cl2CHCHCl 2/140 °C/33h
1.17 Synthesis of 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines
Very recently [112] few 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines (69) were
synthesized as possible antitubercular agents in our group starting from the the allylic aldehyde. Lascorbic acid was at first converted into the allyl alcohols (60), (67) [113] by our modified procedure
[112] which on PCC oxidation gave the respective butenolidyl aldehydes (61) and (68) respectively.
These butenolidyl aldehydes on treatment with β-keto esters or ketones and ammonium acetate in the
presence of tetrabutyl ammonium hydrogen sulphate in ethylene glycol yielded the respective
butenolidedyl 1, 4-dihydropyridine (69) in good yield (Scheme 21). The compounds have shown mild
antitubercular activity against M. tuberculosis H37Rv.
17
Current Organic Chemistry (2009),13, 99-122
HO
OH
HO
O
HO
O
O
ref. 113
RO
OH
H
N
R2
OR
60. R = CH3
67. R = CH 2Ph
1
R1
O
PCC, 4Å MS
CH2Cl 2, 0-30 °C, 1h
R4
OHC
R3
O
O
RO
OR
O
NH4OAc, TBAHS
ß-keto-compound,
ethylene glycol, 90 °C RO
O
OR
61. R = CH3
68. R = CH2Ph
69
Scheme 21.
1.18 Formation of Lactams
2, 3-bis- O-methyl-6-O-p-toluenesulphonyl-L-ascorbic acid (70) reacted with the primary amines
at room temperature to give the 1-alkyl-2,3-dimethoxy-4-hydroxy-4-(hydroxyethyl) but-3-enimide (72)
(Scheme 22) [114].
TsO
OH
O
H 3CO
O
O
RNH 2
OCH 3
O
RNH 2
HO
HO
R
N
O
5 12
4 3
H3CO
H
H 3CO
70
HO
71
O
RNH2
H3CO
OCH3
O
OCH3
O
OCH 3
60
72
Scheme 22.
However, 2, 3-O-dimethyl-5,6-di-O-p-toluenesulphonyl-L-ascorbic acid (58) reacted with the primary
amines to give the 1-alkyl-2,3-dimethoxy-4-hydroxy-4-[1’-(2’-aminoalkyl)ethyl]but-3-enimide (76)
(Scheme 23). Compounds (58) and (70) were prepared by a sequence of reactions from L-ascorbic acid
[114].
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Current Organic Chemistry (2009),13, 99-122
OTs
O
TsO
H 3CO
OTs
O
O
OCH 3
R
N
HO
H3CO
O
H3CO
O
OCH 3
H3CO
NHR
HN
O
74
NHR
R
H3CO
76
HN
O
O
OCH 3
O
OCH 3
73
58
RHN
NHR
R
O
HO
H3CO
OCH 3
OCH 3
75
enol
keto
Scheme 23.
1.19 Nucleoside analogs from L-ascorbic acid
There are several reports on the synthesis and biological activities of L-ascorbic acid based
nucleosides. These compounds show pronounced antitumour, antiviral and anticancer activities.
1.19.1 Novel pyrimidine and purine derivatives of L-ascorbic Acid
Raic´-Malic´ et al [115] have developed the synthesis of few novel pyrimidine derivatives (78-83) of 2,3di-O-benzyl-4,5-didehydro-5,6-dideoxy-L-ascorbic acid by the condensation of pyrimidine bases with
5,6-diacetyl-2,3-dibenzyl-L-ascorbic acid (77) (Scheme 24). Similar condensation of 6-chloropurine bases
with 5-acetyl-6-bromo-2,3-dibenzyl-L-ascorbic acid (ABDA 84) resulted in both the N-9 (85) and N-7
(86) regioisomers, while the reaction of 6-(N-pyrrolyl)purine with ABDA afforded exclusively the N-9
isomer (87) (Scheme 25).
O
O
HN
O
AcO
R5
OAc
O
O
+
N
H
PhH 2CO
R5
HN
i
O
N
O
OCH2Ph
PhH2CO
R5 = H, F, Cl, Br, I, CF3
77
O
OCH 2Ph
78-83
Scheme 24. Reagents and conditions: (i) HMDS, (NH 4)2SO4/argon atmosphere/ref lux/3h;
then trimethyl silyl trif late/dry acetonitrile/55-70 °C/12 h
Compounds (78-83) and (85-87) exhibited cytostatic activities against malignant cell lines: pancreatic
carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma
(Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and human T-lymphocytes
19
Current Organic Chemistry (2009),13, 99-122
(Molt4/C8 and CEM/0), these compounds also displayed antiviral activities against varicellazoster virus
(TK+VZV and TK-VZV) and cytomegalovirus (CMV). Out of the above compound (83), containing a
trifluoromethyl-substituted uracil ring exhibited potent antitumor activity. It has been established that N7- purine regioisomer (86) had greater inhibitory effects on the murine L1210/0 and human CEM/0 cell
lines than the N-9 regio isomer (85). Compound (87) with a 6- pyrroyl substituent had a selective
cytostatic activity against human (Molt4/C8 and CEM/0) cell lines than murine (L1210/0, FM3A/0),
human (MiaPaCa2, MCF7, HeLa, and Hep2) tumor cell lines and normal fibroblasts (Hef522). The
compound (83) exhibited the most potent antiviral activities against TK+VZV, TK-VZV, and CMV, albeit
at concentrations those were only slightly lower than the cytotoxic concentrations.
R6
N
N
R6
Br
N
N
OAc
O
+
N
N
H
O
Cl
N
N
N
N
i
O
PhH 2CO
O
OCH 2Ph
PhH 2CO
84
R6 = Cl,
OCH2Ph
85, 87
R6 = Cl,
N
N
O
N
PhH 2CO
O
OCH 2Ph
86
N
Reagents and conditions: (i) triethyl amine/dry DMF/70 °C/11 h
Scheme 25.
Several 2, 3-di-O-benzyl-6-deoxy-L-ascorbic acid derivatives of pyrimidine bases (93-95) were also
prepared by the condensation of uracil and its 5-trifluromethyl substituted derivatives with 4-(5,6epoxypropyl)-2, 3-O, O-dibenzyl-L-ascorbic acid (92) [116]. The key intermediate 5,6-di-O-acetyl-2,3O,O-dibenzyl-L-ascorbic acid (77) and 4-(5,6-epoxypropyl)-2,3-di-O-dibenzyl-L-ascorbic acid (92), were
prepared from 5,6-O-isopropylidene-L-ascorbic acid (2) [117]. The benzylation of C-2 and C-3 hydroxyl
groups of ascorbic acid with benzyl chloride in DMF provides an intermediate (88) [117,118]. Deblocking
of the 5,6-O,O-protected derivative of L-ascorbic acid (88) with acetic acid in methanol gave 2,3-O,Odibenzyl-L-ascorbic acid (89) [117]. The latter on subsequent acetylation with acetic anhydride in pyridine
and CH2Cl2 gave 87, in an analogous procedure for the preparation of 5-O-acetyl-6-bromo-6-deoxy-2,3O,O-dibenzyl-L-ascorbic acid [118]. 2,3-O,O-Dibenzyl-6-O-tosyl-L-ascorbic acid (90) was obtained by
tosylation of the 6-hydroxy group in 89 using toluene-4-sulfonyl chloride in pyridine [117]. Bromination
of 90 with sodium bromide in acetone gave 6-bromo-2,3-O,O-dibenzyl-L-ascorbic acid (91) [118]. The
later on reaction with sodium carbonate in acetonitrile gave 4-(5,6-epoxypropyl)-2,3-O,O-dibenzyl-Lascorbic acid (92).
20
Current Organic Chemistry (2009),13, 99-122
O
O
O
O
O
HO
O
OH
OH
HO
O
i
ii
O
HPhH 2CO
OCOCH 3
O
O
H3COCO
O
PhH2CO
OCH 2Ph
iii
PhH 2CO
OCH 2Ph
89
88
2
O
OCH2Ph
77
iv
HO
OH
O
PhH2CO
O
HO
OCH 2Ph
92
OH
vi
PhH 2CO
O
91
OH
HO
O
O
v
PhH2CO
OCH 2Ph
O
OCH 2Ph
90
Reagents and conditions: (i) benzyl chloride, K2 CO3 /dry DMF; (ii) 50% acetic acid/MeOH/100 °C/5 h;
(iii) acetic anhydride/pyridine/CH2 Cl2 /-10-24°C/2h;(iv)toluene-4-sulf onyl chloride/CH2Cl2/ pyridine/0-24 °C;
(v) NaBr/acetone/130 °C/7 h; (vi) Na2 CO3/acetonitrile/rt/1 h.
Scheme 26.
Pyrimidine derivatives of 2,3-O,-dibenzyl-6-deoxy-L-ascorbic acid (93-95) were prepared by silylation of
the uracil and its 5-substituted derivatives with 1,1,1,3,3,3-hexamethyldisilazane and subsequent
condensation of the intermediates, thus obtained, with ascorbic acid derivative (92) (Scheme 27).
O
R5
HN
O
HN
O
O
R5
O
O
O
N
i
+
N
H
O
PhH 2CO
OCH 2Ph
PhH2CO
R5 = H, F, CF 3
O
HO
OCH2Ph
93-95
92
Reagents and conditions: (i) HMDS, (NH4) 2SO 4/argon atmosphere/ref lux/3h,
then trimethyl silyl triflate/dry acetonitrile/55-70 °C/12 h.
Scheme 27.
Coupling of (77) with uracil and its 5-substituted derivatives gave pyrimidine derivatives of 2,3-O,Odibenzyl-4,5-didehydro-5,6-dideoxy-L-ascorbic acid (78-79), (83); (Scheme 24) [115]. Debenzylation of
compounds (78-79) and (83) with boron trichloride in CH2Cl2 led to the formation of nucleoside
analogues (96-94) (Scheme 28) [119, 120]. Of all the compounds in the series, compound (98) containing
21
Current Organic Chemistry (2009),13, 99-122
a 5-fluorosubstituted uracil ring showed the most significant antitumor activities against murine leukemia
L1210/0 (IC50 = 1.4 µg/mL), murine mammary carcinoma FM3A/0 (IC50 = 0.78 µg /mL), and, to a lesser
extent, human T-lymphocyte cells Molt4/C8 (IC50 = 31.8 µg /mL) and CEM/0 cell lines (IC50 = 20.9 µg
/mL).
O
R5
HN
R5
78 H
O
N
79 F
83 CF3
O
O
PhH 2CO
OCH 2Ph
O
HN
O
O
R5
N
O
O
PhH 2CO
R5
HN
N
O
O
OH
HO
O
OH
97-99
96
Reagents and conditions: (i) BCl3, CH2Cl 2/-78 °C/2h.
Scheme 28.
Very recently Gazivoda et al [121] synthesized a series of novel C-5 alkynyl substituted pyrimidines (100110) and furo[2,3-d]pyrimidine derivatives (111-121) of L-ascorbic acid by coupling of 5-iodouracil4’,5’-didehydro-5’,6’-dideoxy-L-ascorbic acid with terminal alkynes under the Sonogashira crosscoupling conditions. A number of alkynyl-2’,3’-di-O-benzyl-4’,5’-didehydro-5’,6’-dideoxy-L-ascorbic
acids (IUAA) were prepared by Pd (0) catalyzed reaction condition [122-127]. The 6-alkyl furo[2, 3d]pyrimidine-2-one L-ascorbic acid derivatives (111-121) could be prepared by copper (I)-promoted in
situ cyclization of alkynyl uracil derivatives of ascorbic acid (100-110) (Scheme 29) [124, 128].
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Current Organic Chemistry (2009),13, 99-122
R
O
I
HN
O
O
O
C C R
HN
N
i
O
PhH2CO
O
ii
N
O
O
OCH2Ph
N
PhH 2CO
O
N
O
O
OCH 2Ph
PhH 2CO
100-110
82
O
OCH 2Ph
111-121
Reagents and conditions: (i)
R C CH, iPr2EtN, (PPh 3)4Pd, CuI, DMF, rt; (ii) Et 3N, CuI, 60 °C
R
100, 111
-(CH 2)3CH3
R
106, 117
(CH2) 2
101, 112
-(CH 2)4CH3
102, 113
103, 114
-(CH 2)5CH3
-(CH 2)7CH 3
108, 119
107, 118
Br
104, 115
CH(CH 2)4CH3
OH
109, 120
CH 3
(CH 2)3CH 3
105, 116
(H 2C)3C CH
110, 121
(CH 2)4CH 3
Scheme 29.
The synthesized compounds were evaluated for their cytostatic and antiviral activities. The octynylsubstituted uracil derivative of L-ascorbic acid (102) exhibited the most pronounced cytostatic activities
against all the experimental tumor cell lines (IC50 = 2-12 µM). Pyrimidine derivatives of L-ascorbic acid
containing p-substituted phenylacetylene groups (107-110) possess (IC50 = 3-37 µM) towards all the
experimental tumor cell lines. Among the bicyclic series of compounds, 6-butyl furo[2, 3-d]pyrimidine
derivative (111) and 6-p-bromophenyl furo[2,3-d]pyrimidine derivative (118) showed the best cytostatic
activity (IC50 = 4.5-20 µM), particularly against malignant leukemia (L1210) and T-lymphocyte
(Molt4/C8 and CEM) cells. Compounds (102) and (108) showed specific albeit moderate activity against
cytomegalovirus (CMV, Davis strain), with EC50 = 1.8 and 3.8 µM, respectively, for compounds (102 and
108) at a ~5-fold lower to cytotoxic concentration. Another synthesis for novel C-5 aryl, alkenyl, and
alkynyl substituted uracil derivatives of L-ascorbic acid was developed by Gozivoda et al. [129]. The
compounds were evaluated for their cytostatic and antiviral activity.
1.20. Redox reaction of organic peroxide with L-ascorbic acid
L-ascorbic acid (1) reacts spontaneously with dilauroyl peroxide (122) to produce dehydro
ascorbic acid (123), CO2, lauric acid and undecane [129] (Scheme 30).
23
Current Organic Chemistry (2009),13, 99-122
AcO
(CH3(CH 3)10COO)2
OAc
O
HO
HO
O
122
O
O
Ref . 129
OH
O
OH
OH
OH
123
1
Scheme 30.
The reaction between (1) and (122) was conveniently performed in 85/15 (V/V) isopropyl alcohol under a
nitrogen atmosphere. A constant pH was maintained by a phosphate buffer. The stoichiometry of the
reactants were determined by iodometry. The products were dehydroascorbic acid (123), CO2, and
undecane.
1.21 Unusual molecular complexes from L-ascorbic acid
Certain unusual molecular complexes have been prepared using L-ascorbic acid as starting
material. 2-Methyl-2,5-dimethoxy-2,5-dihydrofuran (125) , an acyclic acetal cis-3-acetyl acrolein (124)
reacts with L-ascorbic acid (1) in aqueous solution to give amorphous 2-(5-methyl-2-furyl)-3-keto-Lgulonolactone-3,6-hemiketal (126) [131]. The reaction mechanism most likely involves cis-3-acetyl
acrolein i.e. 4-keto-cis-2-pentenal (124) as an intermediate (Scheme 30).
H3CO
H 3C
O
OCH3
125
I, H2O
-2CH3OH
H HO
O
O
CH 3
-O
O
O
HO
OH
O
O
O
O
CHOH
CH 2OH
OH
HO
124
H+
H 3C
O
HO
OH
O
HO
-H 2O
O
O
OH
H 3C
O
HO
O
H O
OH
O
OH
126
Scheme 31.
1.22 Reaction of L-ascorbic acid with cis and trans olefinic 1,4-dicarbonyl compounds
L-ascorbic acid (1) reacts with fumaraldehyde (127) to give 2-(1’, 2’-dihydroxy-4’-oxobutyl)-3keto-2’,3-anhydro-L-gulonolactone-1’,4’-cyclohemiacetal-3,6-cycloheketal (128) [132]. The reaction
mechanism (Scheme 32) involves an acid-catalyzed addition of the ascorbic acid (1) to the carbonyl
carbon of fumaraldehyde to give an intermediate (129). This is followed by a Michael addition of the C-3
oxygen at the β-carbon of the α,β-unsaturated hydroxybutenal moiety, attached to C-2 in the compound
(129). Synchronous hemiketal ring closure between C-6 hydroxyl and C-3 of the ascorbate skeleton leads
to an intermediate (130) (Scheme 31). Finally, hemiacetal formation between the two, originally terminal,
carbons of the fumaraldehyde moiety concludes the process to give compound 128.
24
Current Organic Chemistry (2009),13, 99-122
O
HO
O
HO
OH
OH
HO
O
HO
O
OH
127
O
O
O
O
O
OH
HO OH O
CH
O
O
O
OH
130
129
1
HO
O
OH
O
O
O
O
OH
128
Scheme 32.
1.23 L-Ascorbic Acid as a Michael Donor
L-ascorbic acid undergoes Michael reaction with α,β-unsaturated aldehydes, ketones, nitriles and
alicyclic enones to give a variety of organic compounds of great biological significance. Selected
reactions are described in the succeeding sections.
1.23.1 Michael reaction with α,β-unsaturated aldehydes and ketones
L-ascorbic acid (1) undergoes Michael reaction with acrolein (131a) and methyl vinyl ketone
(131b) to give C-2 alkylated derivatives of L-ascorbic acid (132a) and (132b) (Scheme 33) [132(a-b)].
O
O OH O
HO
R
R
O
O
O
+
HO
HO
OH
O
OH
OH
131a , R = H
131b, R = CH 3
1
132a, R = H
132b, R = CH3
Scheme 33.
1.23.2 Michael reaction with alicyclic enones
Michael addition of L-ascorbic acid and 2-cyclohexen-1-one 133 leads to the formation of two
C-3’ epimers (134) and (135) of 2-(1’-keto-3’-cyclohexyl)-3-keto-L-gulonolactone-3,6-cyclohemiketal
[133] (Scheme 34).
25
Current Organic Chemistry (2009),13, 99-122
O
O
O
HO
OH
O
O
+
HO
133
OH
OH O
H 2O/ H+
O
HO
O
OH
+
O
HO
O
OH
OH
1
134
O
135
Scheme 34.
Similarly reaction of (1) and 2-cyclopentene-1-one (136) gives two epimers (137) and (138) of 2-(1’-keto3’-cyclopentyl)-3-keto-L-gulonolactone-3,6-cyclohemiketal [133] (Scheme 35).
O
OH O
OH O
OH
O
HO
O
O
O
H2O/H+
O
O
HO
HO
+
+
O
O
HO
OH
OH
OH
136
1
137
138
Scheme 35.
1.23.3 Michael reaction with tigolyl cyanide
The Michael addition of tigolyl cyanide (139) [134] is initiated by ascorbic acid involving
protonation of tigolyl cyanide followed by conjugate addition of ascorbate anion to give α, and β- enols
(142 and 143), which tautomerize to the respective acyl cyanides (144 and 145) respectively. The latter on
ring closure leads to tricyclic products 146 and 147. During ring closure the major product, piptosidin
(146) is formed due to steric encumberment of C-3 methyl and C-5 hydroxyl in (143) (Scheme 36).
26
Current Organic Chemistry (2009),13, 99-122
HO
O
OH
O
HO
O
OH
+
R1
CN
O
H 2O
O
OH
O R
1
NC
R2
R1
O
OH
142. R 2 = a
143. R 2 = b
R1
R2
OHO
O
R2 OH
O
OH
144. R 1 = b R 2 = a
145. R 1 = a R 2 = b
O
OH
R1
HO
OH O
O
O
R2
O
O
CN
141
HO
O
R1
140
139
NC
O
+
R2
1
OH+
OH
HO
O
+
O
O
OH
146
R2
OH
O
O
OH
147
Scheme 36.
.
1.24 L-Ascorbic acid as a Chiral Synthon
Since L-ascorbic acid possesses two chiral and several pro-chiral centers, significant work has
been done on its chiral chemistry involving its application in various asymmetric synthesis leading to
access several commercially unavailable and highly functionalized chiral synthons. Several of such chiral
synthons including bicyclic alkylidene-dimethoxy butenolides, glycerol acetonides, threitols, erythreitol
and a series of hydroxyl lactone have been prepared starting with L-ascorbic acid [135-152]. A few of
them are described briefly below.
1.24.1 Synthesis of (R)-Glycerol acetonide
Jung et al. [135] have synthesized (R)-glyceroyl acetonide [153-155] from L-ascorbic acid as
shown in (Scheme 37). Treatment of 5,6-O-isopropylidene ascorbic acid (2) with 1 eq. of sodium
borohydride presumably reduces ene-diol functionality followed by the cleavage of the borate esters and
the lactone with excess of sodium hydroxide. The neutralization of reaction mixture to pH 7 produces
acetonide carboxylate (148). The latter on oxidation with 3.5 eq. of Pb(OAc)4 led to the cleavage of all the
glycol bonds and produces (S)-glyceraldehyde acetonide (149) in solution. Due to its instability 149 was
immediately reduced with excess of sodium borohydride to give (R)-glycerol acetonide (150) in good
yield.
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Current Organic Chemistry (2009),13, 99-122
O
O
O
OH
(1) NaBH4
(2) NaOH
O
O
O
HO
(3) H+ pH= 7
(1) NaBH 4
EtOAc
O
CHO
OH
OH
COO- Na+
OH
2
O
O
Pb(OAc)4
O
(2) NaOH
OH
149
148
150
Scheme 37.
Marco et al. [146] have described the synthesis of the most useful 1,2-O-isopropylidene-L-threitol (149a)
[156], L-(S)-glyceraldehyde (149) and L-(R)-glycerol acetonides (150) [157] starting from L-ascorbic
acid successfully as shown in Scheme 38.
Ozonolysis of 5,6- O-isopropylidene ascorbic acid 1 followed by reduction with LiAlH4 led to formation
of a chiral diol. The latter on lead tetraacetate oxidation gives the intermediate aldehyde (149), which on
reduction with NaBH4 gives the required product (150).
O
O
O
MeO
O
OMe
57
(i)
O
O
(ii)
OH
O
O
CHO
HO
149
149 a
O
O
OH
150
Reagents and conditios: (i) O 3, CH 2Cl 2, -78 °C, 15 min; then evaporation, LAH, THF, 0 °C - r.t, overnight
(ii) Pb(OAc)4, CH2Cl 2, K 2CO3 (iii) NaBH 4, EtOH
Scheme 38.
1.24.2 Synthesis of butane-1,2-diacetal protected glyceraldehyde: Butane-1,2-diacetal glyceralehyde
has been prepared from L-ascorbic acid as shown below in scheme 39.
28
Current Organic Chemistry (2009),13, 99-122
HO
OMe
OH
O
HO
O
OH
HC(OMe)3
MeOH, BF 3.THF
OO
OMe
O
HO
O
OH
(1) H 2O2, K 2CO3
(2)Me2SO4
NaBH 4
i-PrOH, 60 °C
OMe
OO
OH
HO
OMe
O
O
OMe
152
151
1
OMe
O
OH NaIO , MeOH/H O
4
2
then NaHCO 3, Br2
OMe
O
O
O
OMe
OMe
OMe
153
155
NaIO4,
CH 2Cl2
OMe
O
O
H
O
OMe
154
Scheme 39.
Ascorbic acid on reaction of butan 2,3-dione and trimethyl orthoformate in BF3.THF led to formation of
5,6-O-protected ascorbic acid derivative (151) which on oxidation with hydrogen peroxide in presence of
K2CO3 followed by esterification with dimethyl sulphate led to the formation of an intermediate (152)
[158,137,140]. The later on reduction with sodium borohydride resulted in a diol (153), which was
oxidized with NaIO4 to afford butane-1,2-diacetal protected glyceraldehyde (154) [159]. Alternatively,
oxidative cleavage of the crude diol (153) with sodium metaperiodate in methanol-water followed by
bromine oxidation of the methyl hemiacetal [160] gave the ester (155) (Scheme 39).
1.24.3 Synthesis of L-glyceric acid
Emmons et al. [145] described a facile route towards the synthesis of optically pure L-glyceric
acids starting from L-ascorbic acid (1). The key step is a ruthenium catalyzed oxidative cleavage of the αhydroxy acid (157a and 157b) as shown in scheme 40.
29
Current Organic Chemistry (2009),13, 99-122
HO
O
OH
O
O
HO
(i)
OH
O
O
O
HO
1
OH
(ii)
O
OH
OH
O
R
O
R
(iii)
157a, 157b
156a, 156b
OH
O
O R
O R
158a, 158b
a : R = CH3
b : R = -(CH 2)5Reagents and condition: (i) (a) 2,2-dimethoxy propane, acetone, SnCl2 (cat.), ref lux, 5 min.
(b) 1,1-dimethoxycyclohexane, EtOAc, SnCl2 (cat.), reflux, 30 min.
(ii) H2O 2, CaCO 3; (iii)NaOCl, RuCl3 (cat.), pH = 8, RT, 30-60 min.
Scheme 40.
1.24.4 Synthesis of a Bicyclic Proline Analogue
Trabocchi et al. [161] synthesized a bicyclic α-amino acid with endo carboxyl (164) and exo
carboxyl groups (171) starting from L-ascorbic acid. The latter was sequentially converted to the triflate
(160), which on reaction with amino acetaldehyde dimethyl acetal (161) gave the intermediate (162)
(Scheme 40). The latter on F-moc protection of -(NH)- group gave an urethane derivative (163) which on
acid catalyzed cyclization [162] afforded the bicyclic α-amino acid with an endo carboxyl group (164).
OMe
H 2N
OH
HO
O
O
161 OMe
O
O
Tf 2O, Py
O
O
ref 137
DIPEA
3 steps
HO
Tf
O
HO
OH
COOMe
COOMe
1
159
MeO
O
MeO
O Fmoc-Cl
2,6-lutidine
160
MeO
O
MeO
HN
COOMe
O
TFA
Fmoc N O
O
HOOC
Fmoc
N
162
COOMe
163
164
Scheme 41.
Formal inversion of the configuration at the C-2 stereocenter in the compound (159) gives (171), the
corresponding diastereomer of (164) carrying the carboxyl group at 2-exo position as shown in (scheme
42).
30
Current Organic Chemistry (2009),13, 99-122
O
O
O
O
ref 163
O
Tf 2O, Py
159
NaHCO 3
MeOH
165. R = ClCH 2CO
166. R = H
OMe
Fmoc-Cl
O
O
2,6-lutidine MeO
N
Fmoc
COOMe
TFA
O
HN
COOMe
167
168
Fmoc N O
O
4 M-HCl-MeCN
O
ref lux, 16 h
Fmoc N O
HOOC
MeOOC
169
O
MeO
COOMe
COOMe
COOMe
DIPEA
Tf O
RO
HO
OMe
161
O
170
171
Scheme 42.
Conclusion: L-ascorbic acid, commonly known as vitamin-C occurs in many natural flora and fauna. Its
biosynthesis in plants has been studied in great detail to give different possible pathways. This small
molecule apart from being used as vitamin exhibit potent antioxidant activity against several oxidants, the
antioxidant activity of the molecule has been exploited in developing several ailments for human beings.
Further, its application in the synthesis of large number of chemotherapeutic agents such as antileukemic,
anticancer, immunomodulatory, antiviral and antibacterial agents has also been elucidated. Importance of
chiral synthons in organic and medicinal chemistry is of vital importance. This review illustrates the
application of L-ascorbic acid to access chiral auxiliaries of tremendous importance in bioorganic
chemistry. The scope of this polyhydroxylated tetranolactone in bioorganic and biochemistry is wide and
posses tremendous potential. The scope of this small organic molecule in development of new chemistry,
potent chemotherapeutics and important materials is very wide and the studies carried out so far is only
small fraction of the scope left.
Acknowledgements: The present manuscript is CDRI communication No 7513. Authors thank DRDO
New Delhi and CSIR New Delhi for financial assistance in the form of a grant in aid and fellowships.
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Table 1. Physical properties of L-ascorbic acid
Property
Appearance
Comments
White, odorless, crystalline solid
with sharp acidic state
C6H8O6/ 176.13 g/mol
190-192 °C
1.65 g/cm3
~3 (5 mg/ml); ~2 (50 mg/ml)
4.17
11.57
First stage: E1O + 0.166 V(pH 4)
Emax (1%. 1cm), 695 at 245 nm (undissociated
form)
Emax (1%. 1cm), 940 at 265 nm (monodissociated
form)
[α]D at 25 °C = +20.5° to 21.5°
(C = 1 in water)
Formula/ molar mass
Melting point
Density
pH
pK1
pK2
Redox Potential
Spectral properties
UV pH2
Spectral properties
UV pH6.4
Optical rotation
37
Current Organic Chemistry (2009),13, 99-122
Water
95% Ethanol
Propylene glycol
Glycerol
Fats and oil Solvents: ether,
chloroform, benzene, petroleum
ether etc.
[α]D at 23 °C = +48° (C = 1 in methanol)
Solubility (g/ml)
0.33
0.033
0.05
0.01
insoluble
38